The overall goal of this project is to understand the association between kidney disease and declines in physical function in HIV infection. Kidney disease is one of the most common non-infectious diseases occurring among the HIV-infected population, affecting up to one-third of HIV-infected persons. In the general population, kidney disease has been associated with frailty, a state of poor functional reserve and diminished capacity to respond to stressors. Kidney disease is associated with systemic changes that may contribute to functional decline and co-morbid conditions which, in turn, lead to significant risk for mortality; however, the pathways by which kidney disease may impact physical function, especially in the context of HIV infection and antiretroviral treatment, need further study. One promising pathway centers around two novel proteins, klotho and fibroblast growth factor-23 (FGF-23). Klotho is a newly discovered hormone which is primarily produced in the kidneys and has been associated with aging and premature death in mouse models. Its role in human aging has not been well-delineated. In the kidneys, klotho serves as a co-receptor for FGF-23, a protein that rises steadily with kidney disease progression and has been associated with cardiovascular disease, incident chronic kidney disease, and death in the general population. To address these key issues, we propose to perform a study of HIV-infected and HIV-uninfected men and women nested within the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) with these specific aims: 1) to evaluate whether markers of kidney injury and kidney function are associated with soluble klotho and FGF-23 levels in HIV-infected and HIV-uninfected individuals; and 2) to determine the associations of soluble klotho and FGF- 23 with physical function in HAART-treated HIV-infected and HIV-uninfected individuals. Using well- characterized and diverse cohorts of HIV-infected individuals with internal HIV-uninfected reference populations, the proposed studies will provide novel data and fill a large gap in our understanding of the associations between kidney disease, klotho, FGF-23, and functional decline in HIV-infection.